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Chagas disease (CD), which is caused by Trypanosoma cruzi and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the search for new therapeutic options is urgent. In this study, nitroazole and azole compounds were synthesized and underwent molecular modeling, anti- T. cruzi evaluations and nitroreductase enzymatic assays. The compounds were designed as possible inhibitors of ergosterol biosynthesis and/or as substrates of nitroreductase enzymes. The in vitro evaluation against T. cruzi clearly showed that nitrotriazole compounds are significantly more potent than nitroimidazoles and triazoles. When their carbonyls were reduced to hydroxyl groups, the compounds showed a significant increase in activity. In addition, these substances showed potential for action via nitroreductase activation, as the substances were metabolized at higher rates than benznidazole (BZN), a reference drug against CD. Among the compounds, 1-(2,4-difluorophenyl)-2-(3-nitro-1 H -1,2,4-triazol-1-yl)ethanol ( 8 ) is the most potent and selective of the series, with an IC 50 of 0.39 µM and selectivity index of 3077; compared to BZN, 8 is 4-fold more potent and 2-fold more selective. Moreover, this compound was not mutagenic at any of the concentrations evaluated, exhibited a favorable in silico ADMET profile and showed a low potential for hepatotoxicity, as evidenced by the high values of CC 50 in HepG2 cells. Furthermore, compared to BZN, derivative 8 showed a higher rate of conversion by nitroreductase and was metabolized three times more quickly when both compounds were tested at a concentration of 50 µM. The results obtained by the enzymatic evaluation and molecular docking studies suggest that, as planned, nitroazole derivatives may utilize the nitroreductase metabolism pathway as their main mechanism of action against Trypanosoma cruzi. In summary, we have successfully identified and characterized new nitrotriazole analogs, demonstrating their potential as promising candidates for the development of Chagas disease drug candidates that function via nitroreductase activation, are considerably selective and show no mutagenic potential.

Infectious diseases are among the leading causes of death worldwide, especially in developing countries. The historical lack of interest of the pharmaceutical industry in developing new drugs against many of these diseases, such as tuberculosis, leishmaniasis, Chagas disease, sleeping sickness, and fungal infections, has left millions of individuals dependent on old treatments that are often ineffective and present different adverse effects. In this sense, new substances against these diseases must be identified. A class of substances that has stood out in the search for new drugs against these diseases is azole derivatives. Within this class, the 3-nitro-1,2,4-triazole nucleus has attracted increasing interest due to its potential, specifically when compared to the 1,2,4-triazole nucleus without the presence of the nitro group, and also in relation to the 2-nitroimidazole nucleus, showing greater potency and selectivity against different etiological agents. This is even more relevant considering that 3-nitro-1,2,4-triazolic substances can promote their activity through different mechanisms of action, such as the inhibition of ergosterol biosynthesis and also via activation by the nitroreductase enzyme, which can avoid the development of cross-resistance. Therefore, in this review, the medicinal chemistry of nitrotriazoles is discussed through the analysis of their potential in terms of biological activity against the etiological agents of several diseases, such as Chagas disease, sleeping sickness and leishmaniasis, caused by kinetoplastid parasites, tuberculosis, caused by the mycobacteria Mycobacterium tuberculosis, and against different species of pathogenic fungi. In addition, aspects related to enzymatic activities, molecular modeling and organic synthesis of these substances are also addressed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)